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Data uncertainty has a great impact on portfolio selection. Based on the popular mean-absolute deviation (MAD) model, we investigate how to make robust portfolio decisions.In this paper, a novel Wasserstein metric-based data-drive...
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Data uncertainty has a great impact on portfolio selection. Based on the popular mean-absolute deviation (MAD) model, we investigate how to make robust portfolio decisions.In this paper, a novel Wasserstein metric-based data-driven distributionally robust mean-absolute deviation (DR-MAD) model is proposed. However, the proposed model is nonconvex with an infinite-dimensional inner problem. To solve this model, we prove that it can be transformed into two simple finite-dimensional linear programs. Consequently, the problem can be solved as easily as solving the classic MAD model. Furthermore, the proposed DRMAD model is compared with the 1/N, classic MAD and mean-variance model on S&P 500 constituent stocks in six different settings. The experimental results show that the portfolios constructed by DR-MAD model are superior to the benchmarks in terms of profitability and stability in most fluctuating markets. This result suggests that Wasserstein distributionally robust optimization framework is an effective approach to address data uncertainty in portfolio optimization.
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Background Liver fibrosis and fibrosis‐related hepatocarcinogenesis are a rising cause for morbidity and death worldwide. Although transforming growth factor‐β (TGF‐β) is a critical mediator of chronic liver fibrosis, targeti...
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Background Liver fibrosis and fibrosis‐related hepatocarcinogenesis are a rising cause for morbidity and death worldwide. Although transforming growth factor‐β (TGF‐β) is a critical mediator of chronic liver fibrosis, targeting TGF‐β isoforms and receptors lead to unacceptable side effect. This study was designed to explore the antifibrotic effect of Compound kushen injection (CKI), an approved traditional Chinese medicine formula, via a therapeutic strategy of rebalancing TGF‐β/Smad7 signaling. Methods A meta‐analysis was performed to evaluate CKI intervention on viral hepatitis‐induced fibrosis or cirrhosis in clinical randomized controlled trials (RCTs). Mice were given carbon tetrachloride (CCl _(4)) injection or methionine‐choline deficient (MCD) diet to induce liver fibrosis, followed by CKI treatment. We examined the expression of TGF‐β/Smad signaling and typical fibrosis‐related genes in hepatic stellate cells (HSCs) and fibrotic liver tissues by qRT‐PCR, Western blotting, RNA‐seq, immunofluorescence, and immunohistochemistry. Results Based on meta‐analysis results, CKI improved the liver function and relieved liver fibrosis among patients. In our preclinical studies by using two mouse models, CKI treatment demonstrated promising antifibrotic effects and postponed hepatocarcinogenesis with improved liver function and histopathologic features. Mechanistically, we found that CKI inhibited HSCs activation by stabilizing the interaction of Smad7/TGF‐βR1 to rebalance Smad2/Smad3 signaling, and subsequently decreased the extracellular matrix formation. Importantly, Smad7 depletion abolished the antifibrotic effect of CKI in vivo and in vitro. Moreover, matrine, oxymatrine, sophocarpine, and oxysophocarpine were identified as material basis responsible for the antifibrosis effect of CKI. Conclusions Our results unveil the approach of CKI in rebalancing TGF‐β/Smad7 signaling in HSCs to protect against hepatic fibrosis and hepatocarcinogenesis in both preclinical and clinical studies. Our study suggests that CKI can be a candidate for treatment of hepatic fibrosis and related oncogenesis.
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Despite the remarkable clinical efficacy of cancer immunotherapy, considerable patients fail to benefit from it due to primary or acquired resistance. Tumours frequently hijack diverse epigenetic mechanisms to evade immune detecti...
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Despite the remarkable clinical efficacy of cancer immunotherapy, considerable patients fail to benefit from it due to primary or acquired resistance. Tumours frequently hijack diverse epigenetic mechanisms to evade immune detection, thereby highlighting the potential for pharmacologically targeting epigenetic regulators to restore the impaired immunosurveillance and re-sensitise tumours to immunotherapy. Herein, we demonstrated that KDM4-targeting chemotherapeutic drug JIB-04, epigenetically triggered the tumour-intrinsic innate immune responses and immunogenic cell death (ICD), resulting in impressive antitumour effects. Specifically, JIB-04 induced H3K9 hypermethylation through specific inhibition of the KDM4 family (KDM4A–D), leading to impaired DNA repair signalling and subsequent DNA damage. As a result, JIB-04 not only activated the tumour-intrinsic cyclic GMP-AMP synthase (cGAS)-STING pathway via DNA-damage-induced cytosolic DNA accumulation, but also promoted ICD, releasing numerous damage-associated molecular patterns. Furthermore, JIB-04 induced adaptive resistance through the upregulation of programmed deathligand 1 (PD-L1), which could be overcome with additional PD-L1 blockade. In human tumours, KDM4B expression was negatively correlated with clinical outcomes, type I interferon signatures, and responses to immunotherapy. In conclusion, our results demonstrate that targeting KDM4 family can activate tumour-intrinsic innate sensing and immunogenicity, and synergise with immunotherapy to improve antitumour outcomes.
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Background Gallbladder cancer (GC) is a malignant disease characterized with highly cellular heterogeneity and poor prognosis. Determining the intratumoral heterogeneity and microenvironment (TME) can provide novel therapeutic str...
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Background Gallbladder cancer (GC) is a malignant disease characterized with highly cellular heterogeneity and poor prognosis. Determining the intratumoral heterogeneity and microenvironment (TME) can provide novel therapeutic strategies for GC. Methods We performed the single‐cell RNA sequencing on the primary and lymph node metastatic gallbladder tumors and the adjacent normal tissues of five patients. The transcriptomic atlas and ligand–receptor‐based intercellular communication networks of the single cells were characterized. Results The transcriptomic landscape of 24,887 single cells was obtained and characterized as 10 cellular clusters, including epithelial, neuroendocrine tumor cells, T&NK cells, B cells, RGS5+ fibroblasts, POSTN+ fibroblasts, PDGFRA+ fibroblasts, endothelial, myeloid cells, and mast cells. Different types of GC harbored distinct epithelial tumor subpopulations, and squamous cell carcinoma could be differentiated from adenocarcinoma cells. Abundant immune cells infiltrated into adenocarcinoma and squamous cell carcinoma, rather than neuroendocrine neoplasms, which showed significant enrichment of stromal cells. CD4+/FOXP3+ T‐reg and CD4+/CXCL13+ T helper cells with higher exhausting biomarkers, as well as a dynamic lineage transition of tumor‐associated macrophages from CCL20 ~(hi)/CD163 ~(lo), CCL20 ~(lo)/CD163 ~(hi) to APOE+, were identified in GC tissues, suggesting the immunosuppressive and tumor‐promoting status of immune cells in TME. Two distinct endothelial cells (KDR+ and ACKR1+), which were involved in angiogenesis and lymphangiogenesis, showed remarkable ligand–receptor interactions with primary GC cells and macrophages in gallbladder tumors. Conclusions This study reveals a widespread reprogramming across multiple cell populations in GC progression, dissects the cellular heterogeneity and interactions in gallbladder TME, and provides potential therapeutic targets for GC. Abundant immune cells in adenocarcinoma and squamous cell carcinoma while stromal cells in neuroendocrine neoplasms were enriched. Immunosuppressive microenvironment characterized as exhausted T cells and APOE+ macrophages. Endothelial cells (KDR+ and ACKR1+) indicated that angiogenesis and lymphangiogenesis were involved in GC. There were remarkable ligand–receptor interactions between endothelial, primary GC cells, and macrophages.
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This paper evaluates the influence of contact pressure on the surface contact state, fretting damage degradation mechanism, crack initiation and propagation characteristics, and fretting fatigue life of A319-T6 cast aluminum alloy...
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This paper evaluates the influence of contact pressure on the surface contact state, fretting damage degradation mechanism, crack initiation and propagation characteristics, and fretting fatigue life of A319-T6 cast aluminum alloy in fretting fatigue test using bridge-type fretting pad. For a certain range of contact pressure, the fretting fatigue life exhibits a trend of increasing and subsequently decreasing with increasing contact pressure. With finite element analysis, the fretting contact region can be divided into two characteristic zones according to the dynamic evolution of the contact status within one fatigue cycle. The contact pressure affects both the distribution of the two characteristic zones as well as the relative slip range, which results in distinct fretting damage mechanisms. The nucleation characteristics and propagation paths of fatigue cracks under three typical contact pressures were analyzed considering the effects of fretting damage and heterogeneous microstructures of the alloy, accounting for the contact pressure dependency of the fretting fatigue life.
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The effect of hot isostatic pressing (HlPing)-induced porosity difference on the fatigue behavior and fracture mechanism of A319 aluminum alloy under uniaxial and nonproportional multiaxial loading is investigated. Non-HIPed alloy...
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The effect of hot isostatic pressing (HlPing)-induced porosity difference on the fatigue behavior and fracture mechanism of A319 aluminum alloy under uniaxial and nonproportional multiaxial loading is investigated. Non-HIPed alloy exhibits weaker nonproportional additional hardening capacity than HIPed alloy, which is ascribed to the nonproportional multiaxial loads that enhance the cyclic softening induced by casting pores. Additional plastic damage caused by nonproportional multiaxial loads is highly susceptible to HIPing. Torsional loads trigger the tension-compression asymmetry of the axial stress response during nonproportional multiaxial fatigue. Multiaxial fatigue life is more sensitive to HIPing at minor total strain amplitudes. The rapid bridging among adjacent pores serves as the preferred channel for fatigue crack propagation. Nonproportional multiaxial loads improve the probability of encountering pores during fatigue crack initiation and propagation.
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Peptidyl-prolyl isomerase Pin1 is crucial for cell proliferation, but its role in pulmonary artery remodeling (PAR) is unclear. In the present study, we aimed to evaluate the expression and contribution of Pin1 in PAR. Treatment w...
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Peptidyl-prolyl isomerase Pin1 is crucial for cell proliferation, but its role in pulmonary artery remodeling (PAR) is unclear. In the present study, we aimed to evaluate the expression and contribution of Pin1 in PAR. Treatment with Pin1 inhibitor Juglone or Pin1-specific siRNAs ameliorated the expression of Pin1 and proliferating cell nuclear antigen (PCNA) in human pulmonary artery smooth muscle cells (PASMCs) in vitro , and Juglone treatment arrested the cell cycle at the G1 phase. Treatment with transforming growth factor β1 (TGF-β1) also enhanced Pin1 expression and PASMC proliferation. Immunohistochemical staining revealed that Pin1 and PCNA expression levels were increased and positively correlated with each other in PAR samples from humans and monocrotaline-treated Sprague-Dawley rats; these proteins were mainly localized in arteries undergoing remodeling, as well as inflammatory cells, and hyperplastic bronchial epithelial cells. Intraperitoneal injection of Juglone also led to morphologic and hemodynamic changes in PAR rats. Additionally, PAR rats displayed higher serum and lung TGF-β1 levels compared with controls, while administration of Juglone to PAR rats suppressed serum and lung TGF-β1 levels. The findings in this study suggest that TGF-β1 and Pin1 constitute a positive feedback loop, which plays an important role in the pathophysiology of PAR.
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Abstract Insufficienct T lymphocyte infiltration and unresponsiveness to immune checkpoint blockade therapy are still major difficulties for the clinical treatment of pancreatic ductal adenocarcinoma (PDAC). Although econazole has...
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Abstract Insufficienct T lymphocyte infiltration and unresponsiveness to immune checkpoint blockade therapy are still major difficulties for the clinical treatment of pancreatic ductal adenocarcinoma (PDAC). Although econazole has shown promise in inhibiting PDAC growth, its poor bioavailability and water solubility limit its potential as a clinical therapy for PDAC. Furthermore, the synergistic role of econazole and biliverdin in immune checkpoint blockade therapy in PDAC remains elusive and challenging. Herein, a chemo‐phototherapy nanoplatform is designed by which econazole and biliverdin can be co‐assembled (defined as FBE NPs), which significantly improve the poor water solubility of econazole and enhance the efficacy of PD‐L1 checkpoint blockade therapy against PDAC. Mechanistically, econazole and biliverdin are directly released into the acidic cancer microenvironment, to activate immunogenic cell death via biliverdin‐induced PTT/PDT and boost the immunotherapeutic response of PD‐L1 blockade. In addition, econazole simultaneously enhances PD‐L1 expression to sensitize anti‐PD‐L1 therapy, leading to suppression of distant tumors, long‐term immune memory effects, improved dendritic cell maturation, and tumor infiltration of CD8+T lymphocytes. The combined FBE NPs and α‐PDL1 show synergistic antitumor efficacy. Collectively, FBE NPs show excellent biosafety and antitumor efficacy by combining chemo‐phototherapy with PD‐L1 blockade, which has promising potential in a precision medicine approach as a PDAC treatment strategy.
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Regarding the new demands and challenges of sixth-generation (6G) mobile communications, wireless networks are undergoing a significant shift from traditional terrestrial networks to space-air-ground-sea-integrated networks. Unman...
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Regarding the new demands and challenges of sixth-generation (6G) mobile communications, wireless networks are undergoing a significant shift from traditional terrestrial networks to space-air-ground-sea-integrated networks. Unmanned aerial vehicle (UAV) communications in complicated mountainous scenarios are typical applications and have practical implications, especially in emergency communications. In this paper, the ray-tracing (RT) method was applied to reconstruct the propagation scenario and then acquire the wireless channel data. Channel measurements are also conducted in real mountainous scenarios for verification. By setting different flight positions, trajectories, and altitudes, channel data in the millimeter wave (mmWave) band was obtained. Important statistical properties, such as the power delay profile (PDP), Rician K-factor, path loss (PL), root mean square (RMS) delay spread (DS), RMS angular spreads (ASs), and channel capacity were compared and analyzed. The effects of different frequency bands on channel characteristics at 3.5 GHz, 4.9 GHz, 28 GHz, and 38 GHz bands in mountainous scenarios were considered. Furthermore, the effects of extreme weather, especially different precipitation, on the channel characteristics were analyzed. The related results can provide fundamental support for the design and performance evaluation of future 6G UAV-assisted sensor networks in complicated mountainous scenarios.
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Summary Fungal infections have emerged as a major global threat to human health because of the increasing incidence and mortality rates every year. The emergence of drug resistance and limited arsenal of antifungal agents further ...
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Summary Fungal infections have emerged as a major global threat to human health because of the increasing incidence and mortality rates every year. The emergence of drug resistance and limited arsenal of antifungal agents further aggravates?the current?situation resulting in a growing challenge in medical mycology. Here, we identified that ponatinib, an FDA‐approved antitumour drug, significantly enhanced the activity of the azole fluconazole, the most widely used antifungal drug. Further detailed investigation of ponatinib revealed that its combination with fluconazole displayed broad‐spectrum synergistic interactions against a variety of human fungal pathogens such as Candida albicans , Saccharomyces cerevisiae and Cryptococcus neoformans . Mechanistic insights into the mode of action unravelled that ponatinib reduced the efflux of fluconazole via Pdr5 and suppressed the expression of the proton pump, Pma1. Taken together, our study identifies ponatinib as a novel antifungal that enhances drug activity of fluconazole against diverse fungal pathogens.
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